How One Scientist’s Misfolded Protein Breakthrough is Saving Lives

What began as a postdoc’s curiosity about protein structures is helping redefine the future treatment of patients with neurodegenerative disease like Alzheimer's, Parkinson's, and ALS.

Jeffery Kelly, PhD, of Scripps Research, transformed basic science into breakthrough therapies by uncovering how misfolded proteins contribute to the conditions that feature telltale protein clumping. His early discoveries laid the groundwork for tafamidis, a small molecule drug for patients with cardiac amyloidosis that became Pfizer’s fourth highest-selling drug in 2024, and inspired a wave of protein-targeting drug development.

Kelly recently received the 2025 Ross Prize in Molecular Medicine, from the Feinstein Institutes for Medical Research and Molecular Medicine in recognition not just for his scientific discoveries but also because of their impact on the practice of medicine. He received the award at Cure in ceremonies on June 4, in conjunction with the New York Academy of Sciences, and lectured about his work at a research symposium.

Misfolded Proteins, Misguided Signals: The Roots of Disease

Amino acids are the building blocks of proteins. But a string of amino acids must contort into just the right shape for a protein to do its job correctly. Protein folding is a complex process and is not 100 percent efficient. When protein folding goes awry, it can lead to deposits of abnormal proteins that cause neurodegenerative diseases such as Alzheimer's and Parkinson's and promote illnesses such as amyloidosis and amyotrophic lateral sclerosis (ALS).

"When we're young, the systems we have to clear out misfolded and aggregated proteins tend to work very well. But as we age, these systems become less efficient. As a consequence, that protein accumulation causes neurodegeneration," Kelly explained.

The genetic evidence supporting the role of protein misfolding and aggregation in neurodegenerative diseases is compelling and backed up by 40 years of data in thousands of published scientific papers.

From a Chance Encounter to a New Field of Discovery

Kelly's interest in protein folding took off when he was a postdoc at The Rockefeller University in the late 1980s. He was exploring the formation of beta sheets — structures that provide strength and shape to proteins. Misfolded beta sheets can aggregate into rigid, sticky amyloid fibrils: long, threadlike protein structures that play a role in diseases involving neurons, the nerve cells in the brain and spinal cord.

"I happened upon a paper on transthyretin and the word amyloid was in the title," Kelly recalled. "I didn't know what it was and I started reading about it." Transthyretin (TTR) is a protein and when it breaks apart, the pieces can misfold and stick together, forming amyloid fibrils. The fibrils can build up and cause damage in organs, including the heart, kidneys, eyes and GI track, and leading to diseases such as TTR amyloidosis.

In subsequent years, Kelly and his team published many of the initial basic scientific research papers showing that conformational changes in TTR were sufficient to promote neurodegenerative diseases. Their studies laid the foundation for the development of medications like tafamidis designed to take aim at protein aggregation.

Targeting the Heart: The First Drug to Stabilize Misfolded TTR

One manifestation of TTR amyloidosis is cardiomyopathy, which is life-threatening if left untreated. The build-up of amyloid deposits in the heart can stiffen its tissues and make it harder to pump effectively. Amyloid deposits can also develop in the peripheral and central nervous systems and other tissues.

Kelly began developing compounds for TTR amyloidosis. He formed the company FoldRx with the late Susan Lindquist, PhD, from MIT, who was developing similar compounds for Parkinson's disease. His lab designed the first drug to target TTR aggregation and showed that it slowed both neurodegeneration and organ deterioration.

Pfizer bought this compound, tafamidis (Vyndamax and Vyndaqel, two different forms of the same active ingredient). It received approval in Europe in 2011 and in the United States in 2019.

Tafamidis slows the progression of TTR cardiac amyloidosis by binding to and stabilizing the TTR protein, preventing it from breaking down and forming amyloid deposits in the heart. Pfizer reported that tafamidis accounted for 9 percent of its total revenue in 2024.

A New Drug Class Emerges: Modulating Protein Aggregation Across Diseases

Another drug that works by targeting protein aggregation is lecanemab (Leqembi), an antibody that slows the progression of Alzheimer's disease. Developed by Swedish neuroscientist Lars Lannfelt, MD, PhD, it is used around the world. Lecanemab — manufactured and marketed by Eisai Co., Ltd. and Biogen Inc. — reduces amyloid-beta plaques in the brain of people with Alzheimer's by binding to amyloid fibrils.

"There are now 10 regulatory agency-approved drugs that slow the progression of neurodegenerative diseases, all the which target protein aggregation as their mechanism," noted Kelly. "It's been a long road, but I think it's clear now that protein misfolding and aggregation-modulating drugs are all we have today to treat neurodegenerative diseases such as Alzheimer's, superoxide dismutase 1 (SOD1)-associated ALS, TTR amyloidosis and light-chain amyloidosis."

Other leading pharmaceutical companies in the protein folding arena include Ionis Pharmaceuticals, which produces Qalsody (tofersen) for SOD1-associated ALS (marketed by Biogen). The company is working on other compounds for Alzheimer's, Huntington's disease and other neurodegenerative diseases.

Alnylam Pharmaceuticals developed vutrisiran (Amvuttra), another drug for TTR cardiomyopathy, using RNAi technology. It is also indicated for the treatment of peripheral nervous system manifestations of TTR amyloidosis.

Among the biotech leveraging misfolded protein are Aggregate Biosciences and Sunbird Bio, which are developing novel diagnostics to detect amyloid aggregates in the blood. Aggregate Biosciences was a finalist for the 2025 XSeed Award, which provides grants of up to $250,000 to New York City minority- and women-led life science and healthcare startups working on novel preclinical drug development projects.

Activating Nature's Clean-Up Crew to Prevent Protein Buildup

Kelly has since co-founded another company, Protego, which is developing first-in-class small molecules that take aim at other diseases caused by aberrant protein folding. One compound for light-chain amyloidosis, a cancer-like protein aggregation disease that affects plasma cells, is in a phase 1 clinical trial.

His approach this time is to design drugs that activate the natural systems that keep us free from protein-aggregation diseases when we're young, including a process called autophagy — a form of recycling in cells.

"I hope that in the last chapter of my academic life, I can make a drug that activates autophagy, because the human genetic data suggest that this will be generally useful for neurodegenerative diseases," he said. "We hypothesize that we can treat these diseases by activating autophagy in elderly people, and we have some small molecules that do that. Now we're working to identify their targets and improve them enough so they can be assessed in clinical trials."

He emphasizes the importance of basic science research for planting the seeds of ideas that eventually generate life-changing medications. "There is no biotech industry without great ideas from academia," Kally asserted. "You never know the impact that basic research is going to have in the clinical pharmacologic marketplace."